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US20100022631A1 - Treatment of hepatic encephalopathy and liver cirrhosis - Google Patents

Treatment of hepatic encephalopathy and liver cirrhosis Download PDF

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Publication number
US20100022631A1
US20100022631A1 US12/429,832 US42983209A US2010022631A1 US 20100022631 A1 US20100022631 A1 US 20100022631A1 US 42983209 A US42983209 A US 42983209A US 2010022631 A1 US2010022631 A1 US 2010022631A1
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treatment
liver
taa
capsaicin
hepatic encephalopathy
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Elliot Berry
Yosefa Avraham
Raphael Mechoulam
Yaron Ilan
Yossi Dagon
Iddo Magen
Nicholas Grigoriadis
Theofilos Poutachidis
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Aristotle University of Thessaloniki
Hadasit Medical Research Services and Development Co
Yissum Research Development Co of Hebrew University of Jerusalem
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Aristotle University of Thessaloniki
Hadasit Medical Research Services and Development Co
Yissum Research Development Co of Hebrew University of Jerusalem
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Priority to US13/162,160 priority patent/US10166202B2/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/658—Medicinal preparations containing organic active ingredients o-phenolic cannabinoids, e.g. cannabidiol, cannabigerolic acid, cannabichromene or tetrahydrocannabinol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • A61K31/09—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon having two or more such linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a composition and methods for the treatment or prevention of hepatic encephalopathy and liver cirrhosis.
  • Cirrhosis is a consequence of acute and chronic liver disease characterized by replacement of liver tissue by fibrotic scar tissue as well as regenerative nodules, leading to progressive loss of liver function. Cirrhosis is most commonly caused by alcoholism, hepatitis C, toxins and fatty liver but has many other possible causes.
  • HE hepatic encephalopathy
  • cerebral dysfunction is heterogeneous ranging from mild neuropsychiatric and psychomotor dysfunction, impaired memory, increased reaction time, sensory abnormalities and poor concentration to severe features such as confusion, stupor, coma and eventually death.
  • Hepatic encephalopathy is caused by disorders affecting the liver including disorders that reduce liver function (such as cirrhosis or hepatitis) and conditions where there is impaired blood circulation in the liver.
  • liver failure induces impaired glucose oxidative pathways and increased lactate synthesis in the brain which results in energy failure.
  • hypoglycemia and hypoxia are also major contributors to the energy failure seen in hepatic encephalopathy.
  • ammonia is considered to play a major role in the pathogenesis of the neuropsychiatric disturbances observed in hepatic encephalopathy.
  • the liver is the major organ for detoxifying ammonia. When the liver fulls the body is incapable of efficiently converting ammonia to urea or glutamine, resulting in systemic hyperammonemia including the brain.
  • the brain lacks an effective urea cycle and therefore relies entirely on glutamine synthesis for the removal of blood-borne ammonia. Since glutamine synthetase is dependent on an adequate level of ATP to amidate glutamate to glutamine, ammonia intoxication results in depletion of brain ATP resources and eventually cell death (Ott et al., 2005; Hardie, 2004). Finally, decreased glucose utilization in the brain may be compensated by mobilization of amino acids to provide carbon skeletons as substrates for energy metabolism. Yet, attempts to balance energy failure at the expense of cerebral proteins may end in destructive brain proteolysis (Hardie and Carling, 1997).
  • AMP-activated protein kinase is an evolutionarily conserved metabolic master switch. AMPK is allosterically activated by 5′-AMP, which accumulates following ATP hydrolysis. Conversely, high ATP antagonizes the activating effects of 5′-AMP on AMPK. AMP binding to AMPK leads to activation of the enzyme by inducing a conformational change exposing threonine-172 in the catalytic domain, which undergoes phosphorylation by an upstream AMPK kinase (AMPKK) (Hawley et al., 1996).
  • AMPKK upstream AMPK kinase
  • Hypothalamic AMPK controls energy balance via regulation of food intake, body weight and glucose and lipid homeostasis (Dagon et al., 2005; Pagotto et al., 2005).
  • Hippocampal AMPK controls cognitive function via regulation of neurogenesis and neuroapoptosis (Dagon et al, 2005).
  • the cannabinoid (CB) system consists of two receptor subtypes.
  • the CB-1 receptors are predominantly found in the brain, while the CB-2 receptors are mostly found in the peripheral tissue (Matsuda, et al., 1990).
  • the main endogenous endocannabinoids are small molecules derived from membrane arachidonic acid, such as anandamide(arachidonoylethanolamide) and 2-arachidonoylglycerol (2-AG) (Iversen, 2000; Berry et al., 2002).
  • D9-tetrahydrocannabinol (THC), the major psychoactive constituent of the Cannabis plant, is a cannabinoid agonist which produces a myriad of complex pharmacological effects (Baker et al., 2003; Avraham et al., 2006). It is now recognized that most of the central effects of endogenous as well as exogenous cannabinoids are mediated through the CB-1 receptor, a family of G-protein-coupled receptors. Cerebral CB-1 receptors are part of the complex mechanisms involved in the control of energy balance via regulation of food intake and body weight (Teixeira-Clerc et al., 2006). The endocannabinoid system has also been demonstrated to exert neuroprotective effects in several types of cerebral insults via regulation of motor control, cognition, emotional responses, motivated behavior and homeostasis (Julien et al., 2005).
  • the endocannabinoid system was shown to have an important role in the pathogenesis of hepatic encephalopathy. Modulation of this system, either by specific antagonists to the CB1 cannabinoid receptor, or by agonists specific for the CB2 receptor, such as HU-308 was shown to be effective (Avraham et al., 2006).
  • the present invention is based on the surprising finding that D9-tetrahydrocannabinol (THC) is effective in the treatment of hepatic encephalopathy.
  • THC D9-tetrahydrocannabinol
  • This finding is surprising in view of the fact that THC was previously known to have about equal affinity both to the CB1 and the CB2 receptors and the above-mentioned Avraham et al, 2006 publication teaches that modulation of the endocannabinoid system is effected either by specific antagonists to the CB1 cannabinoid receptor or by agonists specific for the CB2 receptor.
  • the present invention is further based on the findings that cannabidiol (CBD) and capsaicin are effective in the treatment of hepatic encephalopathy. This finding is also surprising since cannabidiol does not exert its physiological activity through neither of the CB1 or the CB2 receptors while capsaicin is known to act through the vanilloid receptors subtype 1.
  • CBD cannabidiol
  • the present invention relates to a compound selected from D9-tetrahydrocannabinol (THC), cannabidiol or capsaicin, comprising said compound, for prevention, treatment, or both, of hepatic encephalopathy.
  • THC D9-tetrahydrocannabinol
  • cannabidiol cannabidiol
  • capsaicin comprising said compound, for prevention, treatment, or both, of hepatic encephalopathy.
  • the present invention also relates to pharmaceutical composition
  • a compound selected from D9-tetrahydrocannabinol (THC), cannabidiol or capsaicin for prevention, treatment, or both, of hepatic encephalopathy.
  • a method for prevention, treatment, or both, of hepatic encephalopathy comprising administering to a subject in need an effective amount of a compound selected from the group consisting of D9-tetrahydrocannabinol, cannabidiol and capsaicin, is provided.
  • hepatic encephalopathy in the context of the invention, and in accordance with the World Congress of Gastroenterology 1998 in Vienna, refers to all subclasses of the disease as follows: Type A (acute), hepatic encephalopathy associated with acute liver failure; type B (bypass), caused by portal-systemic shunting without associated intrinsic liver disease; and type C (cirrhosis), occurring in patients with cirrhosis.
  • hepatic encephalopathy refers to all durations and characteristics of hepatic encephalopathy and includes episodic, persistent and minimal.
  • minimal encephalopathy refers to patients with cirrhosis who do not demonstrate clinically overt cognitive dysfunction, but who show a cognitive impairment on neuropsychological studies.
  • the evaluation of severity of persistent hepatic encephalopathy is based on the West Haven Criteria for semi-quantitative grading of mental status, referring to the level of impairment of autonomy, changes in consciousness, intellectual function, behavior, and the dependence on therapy, and includes: Grade 1—trivial lack of awareness; euphoria or anxiety; shortened attention span; impaired performance of addition. Grade 2—lethargy or apathy; minimal disorientation for time or place; subtle personality change; inappropriate behavior; impaired performance of subtraction. Grade 3—somnolence to semistupor, but responsive to verbal stimuli; confusion; gross disorientation. Grade 4—Coma (unresponsive to verbal or noxious stimuli).
  • treatment in the context of the present invention refers to at least one of the following: decrease in the severity of at least one undesired side effect associated with the disease; improvement in the overall cognitive function of the treated subject; delay in the progression from one disease stage to the other; shortening the length of an hepatic encephalopathy episode and lengthening the period between episodes.
  • treatment is also meant to refer to preventive or prophylactic treatment—meaning that a person known to have liver dysfunction or to be at risk for developing liver dysfunction (for example, due to hepatitis C) is administered with THC, cannabidiol or capsaicin, even before manifestation of hepatic encephalopathy in order to prevent its occurrence.
  • THC or “D9-tetrahydrocannabinol” are used herein interchangeably for the compound ( ⁇ )-(6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol.
  • This substance may be isolated from the natural source (cannabis), for example, in accordance with the method in Gaoni and Mechoulam (1964) or may be synthetically produced such as dronabinol, which is available as a prescription drug (under the trade name MarinolTM of Unimed Pharmaceuticals, Inc.)
  • the present invention also relates to a compound selected from capsaicin, 2-arachidonoylglycerol (2-AG), HU-308 or cannabidiol for prevention, treatment, or both, of liver cirrhosis.
  • the invention further relates to the use of capsaicin, cannabidiol (CBD), 2-arachidonoylglycerol or HU-308 for the preparation of a medicament for prevention, treatment, or both, of liver cirrhosis.
  • CBD cannabidiol
  • 2-arachidonoylglycerol or HU-308 for the preparation of a medicament for prevention, treatment, or both, of liver cirrhosis.
  • the invention concerns a method for the prevention, treatment, or both, of liver cirrhosis comprising administering to a subject a therapeutically effective amount of capsaicin, cannabidiol, 2-arachidonoylglycerol or HU-308.
  • liver cirrhosis refers to any stage in the development of the pathological condition, from very initial development of fibrotic scar tissue to full-blown liver cirrhosis.
  • diseases or conditions that are known to lead to liver cirrhosis are, but are not limited to: alcoholic liver disease, chronic viral hepatitis (Type B and C), chronic bile duct blockage, metabolic diseases resulting in abnormal storage of copper (Wilson's disease) or iron (Hemochromatosis).
  • Cirrhosis may also be caused by exposure to drugs and toxins, by autoimmune processes such as autoimmune hepatitis, by inherited diseases such as cystic fibrosis and alpha antitrypsin deficiency, and by obesity (so called “fatty liver” or nonalcoholic steatohepatitis). Furthermore, severe reactions to prescription drugs, prolonged exposure to environmental toxins such as arsenic, the parasitic infection schistosomiasis, and repeated bouts of heart failure with liver congestion can all lead to cirrhosis.
  • the treatment may be initiated when a disease is established to stop or slow disease progression.
  • a disease e.g. hepatitis, excessive consumption of alcohol and obesity
  • capsaicin, cannabidiol, 2-AG or HU-308 may be given in a preventive prophylactic manner to prevent or delay the onset of cirrhosis.
  • the level of significance of differences between treatment groups is designated with one, two or three asterisks(s).
  • FIG. 1 shows D9-tetrahydrocannabinol (THC)-induced AMPK activation following thioacetamide (TAA)-induced liver failure in mice.
  • THC D9-tetrahydrocannabinol
  • TAA thioacetamide
  • FIGS. 2A-E show that THC activates AMPK and improves impaired brain function in TAA-induced liver failure in mice.
  • Mice were treated with TAA for 5 days, then 0.1 mM THC was administrated daily for 5 days.
  • 2 A Hippocampal AMPK expression and phosphorylation on Thr 172 were analyzed by immunoblotting. P-AMPK, phosphorylated AMPK.
  • 2 B Mice were treated as above and performance in an eight arm maze was measured every day after the THC treatment. AUC, area under the curve.
  • 2 C Activity score.
  • 2 D Neurological score under the same conditions.
  • Catecholamines levels were analyzed by HPLC. DA, dopamine.
  • FIGS. 3A-F show the effect of AICAR and THC treatment on hepatic failure.
  • Mice were treated with TAA or saline and then with 0.5 mM AICAR or 0.1 mg/l THC. Blood plasma was obtained for liver functions analysis.
  • 3 A Ammonia
  • 3 B Bilirubin
  • 3 C alanine transaminase
  • AST aspartate aminotransferase
  • 3 E gamma-glutamyltransferase
  • GTT gamma-glutamyltransferase
  • FIGS. 4A-F depict histopathological changes in the liver after treatment with TAA.
  • FIGS. 5A-B show TAA effect on ( 5 A) alanine transaminase (ALT) and ( 5 B) aspartate aminotransferase (AST) in mice treated with different cannabinoid receptor ligands.
  • FIGS. 6A-B show effect of 2-arachidonoylglycerol (2-AG) and SR141716A on blood ALT ( 6 A) and AST levels ( 6 B) in TAA treated CB2-KO mice.
  • FIGS. 7A-B show that capsaicin significantly reduces both the ALT ( 7 A) and the AST ( 7 B) level in TAA treated mice.
  • FIGS. 8A-F depict glial cell staining at the area of hippocampus in na ⁇ ve animals ( 8 A), and astrogliosis following TAA administration ( 8 B-F).
  • GFAP a marker for glial cells
  • FIGS. 9A-C show that capsaicin significantly improves TAA-induced impaired cognitive function ( 9 A), poor activity performances ( 9 B) and reduced neurological score ( 9 C).
  • FIGS. 10A-B depict the effect of 2-AG treatment of chronic liver failure induced by bile duct ligation (BDL) on cognitive impairment ( 10 A) and motor impairment ( 10 B) relative to Sham operated animals.
  • AUC area under the curve.
  • FIGS. 11A-B depict the effect of cannabidiol (CBD) treatment of chronic liver failure induced by bile duct ligation (BDL) on cognitive impairment ( 11 A) and motor impairment ( 11 ) relative to Sham operated animals.
  • CBD cannabidiol
  • FIGS. 11A-B depict the effect of cannabidiol (CBD) treatment of chronic liver failure induced by bile duct ligation (BDL) on cognitive impairment ( 11 A) and motor impairment ( 11 ) relative to Sham operated animals.
  • AUC area under the curve.
  • FIGS. 12A-B depict the effect of cannabidiol (CBD) treatment of chronic liver failure induced by bile duct ligation (BDL) on IL-1 ⁇ mRNA level in the hippocampus relative to Sham operated animals.
  • 12 A RT-PCR gel separation; 12 B quantification of measurements done on the gel depicted in 12 A.
  • L19 ribosomal protein commonly used as invariant control gene; AUC, area under the curve.
  • FIG. 13 shows the effect of cannabidiol (CBD) treatment of chronic liver failure induced by bile duct ligation (BDL) on oxidative stress in the liver.
  • CBD cannabidiol
  • BDL bile duct ligation
  • AMPK is potently activated in murine models of hepatic encephalopathy. This correlates with the observed hyperammonia and hypoglycemia—two major causes of cerebral energy depletion. Nonetheless, as found in acute hepatotoxicity (caused by TAA), this response decreases with time, and eventually reaches the same level as that of the chronic stress induced by bile duct ligation. Such a cerebral adaptation response fulls to meet the intact brain energy requirements and may be augmented by pharmacological means (AICAR).
  • AICAR pharmacological means
  • AMPK pharmacological activation of AMPK might provide a new strategy for the management of hepatic encephalopathy.
  • unselective drugs such as AICAR, which activate AMPK under normal as well as under stress conditions, are not suitable for clinical use.
  • THC the main active constituent of marijuana, has been repeatedly demonstrated to cause brain dysfunction and neurotoxicity (Mishima et al., 2001). This finding is in line with our observations disclosed herein below of its ability to stimulate AMPK.
  • these studies have used high dosage of THC (1-15 mg/kg), quantities that we found necessary for AMPK activation under normal circumstances.
  • THC could be suitable as a selective agent that could function as a “stress specific drug” by activating AMPK only under pathological conditions.
  • THC which has about equal affinity for the CB1 and CB2 receptor
  • THC transient receptor potential 1 TRPV1
  • capsaicin suggested by Di Marzo et al (1998) to interact with the endocannabinoid system, acts on neural cells via vanilloid receptors subtype 1 (VR1, also known as transient receptor potential 1 TRPV1), a non-selective cation channel, which can be blocked by capsazepine.
  • VR1 vanilloid receptors subtype 1
  • TRPV1 transient receptor potential 1
  • a second compound tested herein to treat the animals is cannabidiol, an active ingredient of Cannabis Sativa devoid of adverse effects related to the CB1 receptor owing to its CB1-independent mechanism of action.
  • Cannabidiol is also a very potent anti-inflammatory agent. It is a finding of the present invention that cannabidiol improves impaired brain and liver function in experimental hepatic encephalopathy in animal models. Furthermore, two additional cannabinoids, 2-AG and HU-308 were shown herein to positively affect liver function in experimental hepatic encephalopathy in animal models.
  • the present invention thus provides a compound selected from D9-tetrahydrocannabinol (THC), cannabidiol and capsaicin for prevention, treatment, or both of hepatic encephalopathy.
  • THC D9-tetrahydrocannabinol
  • cannabidiol cannabidiol
  • capsaicin for prevention, treatment, or both of hepatic encephalopathy.
  • the compound is D9-tetrahydrocannabinol. In another preferred embodiment the compound is cannabidiol. In still another preferred embodiment the compound is capsaicin.
  • the compound may be formulated in any suitable form for administration, preferably in an oral, parenteral, sublingual or intranasal dosage form.
  • D9-tetrahydrocannabinol, cannabidiol and capsaicin are intended for prevention and/or treatment of all subclasses of hepatic encephalopathy as described above, i.e. Type A, Type B or Type C, preferably type A or type C.
  • the present invention further provides a pharmaceutical composition for prevention, treatment, or both, of hepatic encephalopathy comprising a compound selected from D9-tetrahydrocannabinol, cannabidiol and capsaicin and a pharmaceutically acceptable carrier.
  • the present invention also concerns a method for prevention, treatment, or both, of hepatic encephalopathy comprising administering to a subject in need a therapeutically effective amount of a compound selected from D9-tetrahydrocannabinol (THC), cannabidiol and capsaicin.
  • THC D9-tetrahydrocannabinol
  • cannabidiol cannabidiol
  • the present invention relates to a compound selected from capsaicin, 2-arachidonoylglycerol (2-AG), HU-308 or cannabidiol for prevention, treatment, or both, of liver cirrhosis.
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound, selected from capsaicin, 2-arachidonoylglycerol (2-AG), HU-308 or cannabidiol for prevention, treatment, or both, of liver cirrhosis
  • the compound is 2-arachidonoylglycerol. In another preferred embodiment the compound is HU-308. In still another preferred embodiment the compound is capsaicin. In yet another preferred embodiment the compound is cannabidiol.
  • prevention of liver cirrhosis refers herein to preventing or slowing the deterioration of any damage caused to the liver tissue, such as the accumulation of fibrotic scar tissue, by factors known to cause cirrhosis such as, but not limited to, alcoholic liver disease, chronic viral hepatitis type C, chronic viral hepatitis type B, chronic bile duct blockage, Wilson's disease, hemochromatosis, exposures to drug and toxins, autoimmune hepatitis, cystic fibrosis, alpha antitrypsin deficiency, obesity or schistosomiasis.
  • liver cirrhosis prevention of the development of liver cirrhosis can be achieved by treating subjects in need, such as alcoholics, people infected with hepatitis C and obese people, at very early stages of their disease or condition, even before appearance of physical symptoms of liver cirrhosis.
  • the present invention also concerns a method for prevention, treatment, or both, of liver cirrhosis, comprising administering to a subject in need a therapeutically effective amount of a compound selected from capsaicin, 2-arachidonoylglycerol (2-AG), HU-308 or cannabidiol.
  • the present invention further provides a compound selected from cannabidiol (CBD) or capsaicin for prevention, treatment, or both, of hepatic encephalopathy or liver cirrhosis.
  • CBD cannabidiol
  • the invention further provides a pharmaceutical composition for prevention, treatment, or both, of hepatic encephalopathy or liver cirrhosis, comprising cannabidiol or capsaicin and a pharmaceutically acceptable carrier.
  • THC, SR141716A, SR144528 and CBD were provided by Prof. Raphael Mechoulam (Faculty of Medicine and Department of Pharmacology, Hebrew University of Jerusalem).
  • Hepatotoxin thioacetamide (TAA) and capsaicin were obtained from Sigma-Aldrich (Rehovot, Israel).
  • 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) was obtained from Toronto Research Chemicals (TRC).
  • HU-308 was synthesized as described in Hanus et al. (1999).
  • mice Eight- to 10-week old female Sabra mice (29-32 g), obtained from the animal facility of the Hebrew University, Israel, were assigned at random to different groups of 10 mice per cage and were used in all experiments. All cages contained wood-chip bedding and were placed in a temperature-controlled room at 22° C., on a 12 h light/dark cycle (lights on at 07.00 a.m.). The mice had free access to water 24 h a day. The food provided was Purina chow, the animals were maintained in the animal facility (SPF unit) of the Hebrew University Hadassah Medical School, Jerusalem. CB-2 KO mice were provided by Prof. Zimmer, Institute of Molecular Psychiatry, University of Bonn, Germany.
  • mice were sacrificed after treatment by decapitation between 10.00-12.00 a.m. Brains were rapidly removed and were dissected out and kept at ⁇ 70° C.
  • Bile duct ligation (iiia) Bile duct ligation. A midline incision was made under general anesthesia. The common bile duct was localized, doubly ligated, and cut between these two ligatures. In sham animals, a midline incision was performed, but with BDL.
  • TAA TAA.
  • a single dose of 200 mg kg-1 of TAA was injected by the intraperitoneal route (i.p.). 24 hours after injection all animals (including control) were injected (s. c) with 0.5 ml solution of 0.45% NaCl, 5% dextrose and 0.2% KCl in order to prevent hypovolemia, hypokalemia and hypoglycemia. The mice were intermittently exposed to infrared light in order to prevent hypothermia.
  • THC was administered i.p. either alone or with SR141716A on day 6 after TAA administration. Mice were sacrificed 1 h post treatment and analyzed for AMPK level. For the behavioral tests which started on day 6 after TAA administration, THC was administered i.p. during days 6-10. Neurological score, activity and cognitive function were analyzed during these days.
  • Non-specific binding in a Western blot analysis was prevented by immersing the membranes in blocking buffer (5% nonfat dry milk in Tris-buffer saline-Tween 20 (TBS-T)), for 2 h at room temperature. The membranes were then exposed to the indicated antibodies diluted 1:1000 for 1 h at room temperature.
  • Anti-AMPK and phospho-AMPK antibodies were obtained from Cell Signaling.
  • Anti-protein kinase B (AKT) was obtained from Upstate.
  • Anti-actin was from Santa Cruz Biotechnology Inc. (Santa Cruz, Calif.).
  • the blots were rinsed in TBS-T and then incubated with horseradish peroxidase-conjugated goat anti-mouse antibodies (1:10,000; Santa Cruz Biotechnology Inc., Santa Cruz, Calif.) for 1 h at room temperature. Antibody-antigen complexes were visualized by detecting enhanced chemiluminescence with X-ray film.
  • Primers specific for CB1 were GGAGAACATCCAGTGTGGGG [SEQ ID NO: 1] and CATTGGGGCTGTCTTTACGG [SEQ ID NO: 2], for CB2 GGGTCCTCTCAGCATTGATTT [SEQ ID NO: 3], and GTTAACAAGGCACAGCATGGAAC [SEQ ID NO: 4], and for actin CAG CTTCTTTGCAGCTCCTT [SEQ ID NO: 5] and TCACCCACATAGGAGTCCT [SEQ ID NO: 6]. All primers were synthesized by Danyel Biotech, Israel.
  • Neurological function was assessed by a 10 point scale based on reflexes and task performance (Chen et al., 1996): exit from a circle 1 meter in diameter in less than 1 minute, seeking, walking a straight line, startle reflex, grasping reflex, righting reflex, placing reflex, corneal reflex, maintaining balance on a beam 3, 2 and 1 cm in width, climbing onto a square and a round pole. For each task failed or abnormal reflex reaction a score of 1 was assigned. Thus, a higher score indicates poorer neurological function. The neurological score was assessed one day after TAA induction (day 2). The mice were then divided between treatment groups so that each group had a similar baseline neurological score after TAA induction. The post-treatment neurological score was assessed one day after administration of the agonist or the antagonist or the vehicle (day 3).
  • (viii) Activity The activity test was performed on day 4, since in the first 3 days after TAA injection almost no motor activity was observed.
  • One of two methods was utilized: a) an activity apparatus, which consists of a cylindrical chamber (60 cm in diameter) with crossing infrared beams. Locomotor activity was recorded by a counter (attached to the apparatus), that counts the number of beam crossings made by the mice at one-minute intervals. Activity of two mice was measured simultaneously for a five-minute period. Two mice were tested together to lower stress to the minimum. Activity is presented as the mean number of beam crossings in 5 minutes.
  • THC treatment showed a biphasic effect (Sulcova et al., 1998). While low levels of THC (less than 0.1 mg/kg) reduced the level of activated AMPK, higher concentrations exhibited a dose dependent elevation in activated enzyme, reaching a significant activation of AMPK ( FIG. 1 ).
  • THC was tested in TAA treated mice. In this instance THC also demonstrated a biphasic effect.
  • THC Activates AMPK and Improves Impaired Brain Function in Experimental Hepatic Encephalopathy
  • THC which has about equal affinity for the CB1 and CB2 receptor
  • THC which has about equal affinity for the CB1 and CB2 receptor
  • capsaicin suggested by Di Marzo et al (1998) to interact with the endocannabinoid system, acts on neural cells via vanilloid receptors subtype 1 (VR1, also known as transient receptor potential 1 TRPV1), a non-selective cation channel, which can be blocked by capsazepine.
  • VR1 vanilloid receptors subtype 1
  • TRPV1 transient receptor potential 1
  • FIGS. 4A-F depict varying degrees of necrosis which were semi-quantitated as histopathological indices 1-4.
  • TAA treated mice demonstrated increased levels of alanine transaminase (ALT) ( FIG. 5A ) (see also FIG. 3C ) and aspartate aminotransferase (AST) ( FIG. 5B ) (see also FIG. 3D ); treatment of the TAA treated mice with 2-AG—a CB1 agonist, SR141716A—a CB1 antagonist, HU-308—a CB2 agonist, and SR144528—a CB2 antagonist, all significantly reduced ALT and AST levels. Moreover, 2-AG did not counteract the effect of SR141716A or SR144528, and HU-308 did not counteract the effect of SR144528. Thus, the results imply that the agonists/antagonists did not convey their effect specifically through the CB1 or CB2 receptors.
  • CB2 Agonist, but not CB1 Antagonist Treatment Improves Markers of Hepatic Function in CB2-KO Mice
  • FIGS. 7A-B show that indeed, capsaicin significantly reduces both the ALT and the AST level in TAA treated mice.
  • the effect of capsaicin is specifically affected through the VR1 receptor as evidenced by the abolishment of the effect of capsaicin by the VR1 antagonist capsazepine.
  • endocannabioid agonist and antagonist and capsaicin treatment affect the important aspect of hepatic encephalopathy pathology—astrogliosis—TAA treated animals were treated with these compounds and hippocampus was stained for glial cells in na ⁇ ve animals ( FIG. 8A ) and after treatment ( FIGS. 8B-F ).
  • FIG. 8B hepatic encephalopathy induced intensive glial fibrillary acidic protein (GFAP, a marker for glial cells) staining intensity and increased process complexity, i.e. more processes and increased branching ( FIG. 8B ) as compared with na ⁇ ve animals ( FIG. 8 A).
  • FIGS. 10A-B 2-AG effectively reversed cognitive impairments secondary to biliary cirrhosis in mice ( FIG. 10A ), but failed to reverse the motor impairments ( FIG. 10B ) which are also typical to this disorder.
  • Cannabidiol Improves Impaired Brain and Liver Function in Experimental Hepatic Encephalopathy
  • Cannabidiol an active ingredient of Cannabis Sativa devoid of adverse effects related to the CB1 receptor owing to its CB1-independent mechanism of action.
  • Cannabidiol is also a very potent anti-inflammatory agent.
  • BDL bile duct ligation
  • mice Two weeks post-surgery, the cognitive and the motor function of the mice were evaluated. Mice were decapitated 3 weeks post-surgery and their hippocampi were taken for analysis of IL-1b mRNA level by RT-PCR. The results clearly show that cognitive function ( FIG. 11A ) and motor activity ( FIG. 11B ) are impaired by BDL after 2 weeks and is restored by cannabidiol. Also, IL-1 ⁇ mRNA level (normalized to ribosomal protein L19 mRNA levels; a commonly used invariant control gene) in the hippocampus is elevated following BDL and is restored by cannabidiol ( FIGS. 12A-B ).
  • Oxidative stress in liver tissue due to chronic liver failure induced by BDL was assessed by measuring malondialdehyde, a well accepted biomarker for oxidative stress. As can be seen in FIG. 13 , oxidative stress is elevated following BDL and is restored by cannabidiol. As oxidative stress is commonly known to be involved in the development of cirrhosis (Ara et al., 2005) and treatment with cannabidiol reduces the oxidative stress, one can deduce that this treatment will prevent or slow down the development of cirrhosis.
  • bile duct ligation induced cognitive and motor deficits and increased oxidative stress in the liver, which were reversed by cannabidiol.
  • cannabidiol In the hippocampus, which is responsible for learning and memory, there was an up-regulation of IL-1b mRNA following BDL, which was also reversed by cannabidiol, suggesting causal relationship between an inflammatory response in this region and impaired learning.

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WO2015106108A3 (fr) * 2014-01-13 2015-11-12 Kannalife, Inc. Nouveaux 1,3-benzène diols fonctionnalisés et leur procédé d'utilisation pour le traitement de l'encéphalopathie hépatique
US9265458B2 (en) 2012-12-04 2016-02-23 Sync-Think, Inc. Application of smooth pursuit cognitive testing paradigms to clinical drug development
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CA3077624A1 (fr) 2016-10-01 2018-04-05 James Smeeding Compositions pharmaceutiques comprenant une statine et un cannabinoide et leurs utilisations
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US9265458B2 (en) 2012-12-04 2016-02-23 Sync-Think, Inc. Application of smooth pursuit cognitive testing paradigms to clinical drug development
US9380976B2 (en) 2013-03-11 2016-07-05 Sync-Think, Inc. Optical neuroinformatics
WO2015106108A3 (fr) * 2014-01-13 2015-11-12 Kannalife, Inc. Nouveaux 1,3-benzène diols fonctionnalisés et leur procédé d'utilisation pour le traitement de l'encéphalopathie hépatique
CN106456573A (zh) * 2014-01-13 2017-02-22 康纳生物技术有限公司 治疗肝性脑病的新型功能化1，3‑苯二酚及其用法
JP2017507119A (ja) * 2014-01-13 2017-03-16 カンナライフ・サイエンシーズ・インコーポレイテッドＫａｎｎａｌｉｆｅ Ｓｃｉｅｎｃｅｓ， Ｉｎｃ． 新規の官能性１，３−ベンゼンジオール及び肝性脳症を治療するためのそれらの使用方法
US9611213B2 (en) 2014-01-13 2017-04-04 Kannalife Sciences, Inc. Functionalized 1,3-benzene diols and their method of use for the treatment of hepatic encephalopathy
US10004722B2 (en) 2014-01-13 2018-06-26 Kannalife Sciences, Inc. Method for treating hepatic encephalopathy or a disease associated with free radical mediate stress and oxidative stress with novel functionalized 1,3-benzene diols
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